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Adenosine is a critical regulator of inflammation and fibrosis, it affects endogenous cell signaling via binding to the A3 adenosine receptor. FM101 is a potent, highly selective A3 adenosine receptor modulator that has been developed as a treatment for glaucoma and hepatitis. We determined that FM101 is a biased ligand with functional activities both as a G protein agonist and a β-arrestin antagonist. The safety of FM101 was evaluated by administering an acute dose in rats, the results indicated that the approximate lethal dose was greater than 2000 mg/kg. In a subchronic toxicity study, FM101 was administered orally once per day to rats at doses of 250, 500, and 1000 mg/kg/day over a period of 28 days. Abnormal posture, irregular respiration, decreased movement, and ear flushing were observed during the early phase of dosing, and loose stools were observed sporadically among the animals that received 500 and 1000 mg/kg/day. Body weight and food consumption were decreased in one male and one female rat in the 1000 mg/kg/day group during the first 2 weeks of observation. However, there were no test substance-related changes or adverse effects observed during our ophthalmological, clinical chemistry, urine, organ weight, and histopathological analysis. These findings indicate that no observed adverse effect level of FM101 was 1000 mg/kg/day in male and female rats.
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